Pharmaceutical compositions for the coordinated delivery of NSAIDs

ABSTRACT

The present invention is directed to drug dosage forms that release an agent that raises the pH of a patient&#39;s gastrointestinal tract, followed by a non-steroidal anti-inflammatory drug. The dosage form is designed so that the NSAID is not released until the intragastric pH has been raised to a safe level. The invention also encompasses methods of treating patients by administering this coordinated release, gastroprotective, antiarthritic/analgesic combination unit dosage form to achieve pain and symptom relief with a reduced risk of developing gastrointestinal damage such as ulcers, erosions and hemorrhages.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.12/553,804 filed Sep. 3, 2009, now abandoned which is a divisional ofU.S. application Ser. No. 11/129,320 filed May 16, 2005, issued as U.S.Pat. No. 8,206,741 on Jun. 26, 2012 which is a continuation-in-part ofU.S. application Ser. No. 10/158,216, filed on May 31, 2002, issued asU.S. Pat. No. 6,926,907 on Aug. 9, 2005, which claims the benefit ofU.S. provisional application No. 60/294,588, filed on Jun. 1, 2001. Theentire contents of all applications are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions thatprovide for the coordinated release of an acid inhibitor and anon-steroidal anti-inflammatory drug (NSAID). These compositions have areduced likelihood of causing unwanted side effects, especiallygastrointestinal side effects, when administered as a treatment forpain, arthritis and other conditions amenable to treatment with NSAIDs.

BACKGROUND OF THE INVENTION

Although non-steroidal anti-inflammatory drugs are widely accepted aseffective agents for controlling pain, their administration can lead tothe development of gastroduodenal lesions, e.g., ulcers and erosions, insusceptible individuals. It appears that a major factor contributing tothe development of these lesions is the presence of acid in the stomachand upper small intestine of patients. This view is supported byclinical studies demonstrating an improvement in NSAID tolerability whenpatients are also taking independent doses of acid inhibitors (Dig. Dis.12:210-222 (1994); Drug Safety 21:503-512 (1999); Aliment. Pharmacol.Ther. 12:135-140 (1998); Am. J. Med. 104(3A):67S-74S (1998); Clin. Ther.17:1159-1173 (1995)). Other major factors contributing toNSAID-associated gastropathy include a local toxic effect of NSAIDs andinhibition of protective prostaglandins (Can. J. Gastroenterol.13:135-142 (1999) and Pract. Drug Safety 21:503-512, (1999)), which mayalso make some patients more susceptible to the ulcerogenic effects ofother noxious stimuli.

In general, more potent and longer lasting acid inhibitors, such asproton pump inhibitors, are thought to be more protective during chronicadministration of NSAIDs than shorter acting agents, e.g., histamine H₂receptor antagonists (H-2 blockers) (N. Eng. J. Med. 338:719-726 (1998);Am. J. Med. 104(3A):56S-61S (1998)). The most likely explanation forthis is that gastric pH fluctuates widely throughout the dosing intervalwith short acting acid inhibitors leaving the mucosa vulnerable forsignificant periods of time. In particular, the pH is at its lowestpoint, and hence the mucosa is most vulnerable, at the end of the dosinginterval (least amount of acid inhibition) and for some time after thesubsequent dose of acid inhibitor. In general, it appears that when ashort acting acid inhibitor and an NSAID are administeredsimultaneously, NSAID-related mucosal damage occurs before the pH of thegastrointestinal tract can be raised and after the acid inhibitingeffect of the short acting acid inhibitor dissipates.

Although longer lasting agents, such as proton pump inhibitors (PPIs),usually maintain a consistently higher gastroduodenal pH throughout theday, their antisecretory effect may be delayed for several hours and maynot take full effect for several days (Clin. Pharmacokinet. 20:38-49(1991)). Their effect may be diminished toward the end of the usualdosing interval. Intragastric pH rises particularly slowly with thefirst dose in a course of treatment since this class of drugs is entericcoated to avoid destruction by stomach acid. As a result, absorption isdelayed for several hours. Even then, some patients fail to respondconsistently to drugs of this type and suffer from “acid breakthrough”which again leaves them vulnerable to NSAID-associated gastroduodenaldamage (Aliment. Pharmacol. Ther. 14:709-714 (2000)). Despite asignificant reduction in gastroduodenal lesions with the concomitantadministration of a proton pump inhibitor during six months of NSAIDtherapy, up to 16% of patients still develop ulcers, indicating thatthere remains substantial room for improvement (N. Eng. J. Med.338:727-734 (1998)). Thus, the addition of a pH sensitive entericcoating to an NSAID could provide additional protection againstgastroduodenal damage not provided by the H2 blocker or PPI alone. Inaddition, although long acting acid inhibitors may reduce the risk of GIlesions in chronic NSAID users, there are questions about the safety ofmaintaining an abnormally elevated pH in a patient's GI tract for aprolonged period of time (Scand. J. Gastroenterol. Suppl. 178:85-92(1990)).

Recognizing the potential benefits of PPIs for the prevention ofNSAID-induced gastroduodenal damage, others have disclosed strategiesfor combining the two active agents for therapeutic purposes. However,these suggestions do not provide for coordinated drug release or forreducing intragastric acid levels to a non-toxic level prior to therelease of NSAID (U.S. Pat. No. 5,204,118; U.S. Pat. No. 5,417,980; U.S.Pat. No. 5,466,436; and U.S. Pat. No. 5,037,815). In certain cases,suggested means of delivery would expose the gastrointestinal tract toNSAIDs prior to onset of PPI activity (U.S. Pat. No. 6,365,184).

Attempts to develop NSAIDs that are inherently less toxic to thegastrointestinal tract have met with only limited success. For example,the recently developed cyclooxygenase-2 (COX-2) inhibitors show areduced tendency to produce gastrointestinal ulcers and erosions, but asignificant risk is still present, especially if the patient is exposedto other ulcerogens (JAMA 284:1247-1255 (2000); N. Eng. J. Med.343:1520-1528 (2000)). In this regard, it appears that even low doses ofaspirin will negate most of the benefit relating to lowergastrointestinal lesions. In addition, the COX-2 inhibitors may not beas effective as other NSAIDs at relieving some types of pain and havebeen associated with significant cardiovascular problems (JADA131:1729-1737 (2000); SCRIP 2617, pg. 19, Feb. 14, 2001); NY Times, May22, 2001, pg. C1)).

Other attempts to produce an NSAID therapy with less gastrointestinaltoxicity have involved the concomitant administration of acytoprotective agent. In 1998, Searle began marketing Arthrotec™ for thetreatment of arthritis in patients at risk for developing GI ulcers.This product contains misoprostol (a cytoprotective prostaglandin) andthe NSAID diclofenac. Although patients administered Arthrotec™ do havea lower risk of developing ulcers, they may experience a number of otherserious side effects such as diarrhea, severe cramping and, in the caseof pregnant women, potential damage to the fetus.

Another approach has been to produce enteric coated NSAID products.However, even though these have shown modest reductions ingastroduodenal damage in short term studies (Scand. J. Gastroenterol.20: 239-242 (1985) and Scand. J. Gastroenterol. 25:231-234 (1990)),there is no consistent evidence of a long term benefit during chronictreatment.

Overall, it may be concluded that the risk of inducing GI ulcers is arecognized problem associated with the administration of NSAIDs andthat, despite considerable effort, an ideal solution has not yet beenfound.

SUMMARY OF THE INVENTION

The present invention is based upon the discovery of a new method forreducing the risk of gastrointestinal side effects in people takingNSAIDs for pain relief and for other conditions, particularly duringchronic treatment. The method involves the administration of a single,coordinated, unit-dose product that combines: a) an agent that activelyraises intragastric pH to levels associated with less risk ofNSAID-induced ulcers; and b) an NSAID that is specially formulated to bereleased in a coordinated way that minimizes the adverse effects of theNSAID on the gastroduodenal mucosa. Either short or long acting acidinhibitors can be effectively used in the dosage forms. This method hasthe added benefit of being able to protect patients from othergastrointestinal ulcerogens whose effect may otherwise be enhanced bythe disruption of gastroprotective prostaglandins due to NSAID therapy.

In its first aspect, the invention is directed to a pharmaceuticalcomposition in unit dosage form suitable for oral administration to apatient. The composition contains an acid inhibitor present in an amounteffective to raise the gastric pH of a patient to at least 3.5,preferably to at least 4, and more preferably to at least 5, when one ormore unit dosage forms are administered. The gastric pH should notexceed 7.5 and preferably should not exceed 7.0. The term “acidinhibitor” refers to agents that inhibit gastric acid secretion andincrease gastric pH. In contrast to art teaching against the use of H2blockers for the prevention of NSAID-associated ulcers (N. Eng. J. Med.340:1888-1899 (1999)), these agents are preferred compounds in thecurrent invention. Specific H2 blockers that may be used includecimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine orfamotidine. The most preferred acid inhibitor is famotidine present indosage forms in an amount of between 5 mg and 100 mg.

Other preferred agents that may be effectively used as acid inhibitorsare the proton pump inhibitors such as omeprazole, esomeprazole,pantoprazole, lansoprazole, rabeprazole, pariprazole, leminoprazole andtenatoprazole. Examples of particular proton pump inhibitors includeomeprazole, present in unit dosage forms in an amount of between 5 mgand 50 mg; lansoprazole, present in unit dosage forms in an amount ofbetween 5 mg and 150 mg (and preferably at between 5 mg and 30 mg); andpantoprazole, present in unit dosage forms in an amount of between 10 mgand 200 mg. Recently, a newer class of acid inhibitor has been developedwhich competes with potassium at the acid pump. The compounds in thisclass have been referred to as “reversible proton pump inhibitors” or“acid pump antagonists” and may also be used in the present invention.Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazanand soraprazan (see WO9605177 and WO9605199). Other compounds in thisgroup are H-335/25 (AstraZeneca, Dialog file 128, accession number020806); Sch-28080 (Schering Plough, Dialog file 128, accession number009663); Sch-32651 (Schering Plough, Dialog file 128, accession number006883) and SK&F-96067 (CAS Registry no. 115607-61-9).

The pharmaceutical composition also contains a non-steroidalanti-inflammatory drug in an amount effective to reduce or eliminatepain or inflammation. The NSAID may be celecoxib, rofecoxib,lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522,L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID forthe purposes of the present invention), ibuprofen, flurbiprofen,ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac,lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone,diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac,tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamicacid, oxyphenbutazone, azapropazone, and phenylbutazone. The mostpreferred NSAID is naproxen in an amount of between 50 mg and 1500 mg,and more preferably, in an amount of between 200 mg and 600 mg. It willbe understood that, for the purposes of the present invention, referenceto an acid inhibitor, NSAID, or analgesic agent will include all of thecommon forms of these compounds and, in particular, theirpharmaceutically acceptable salts. The amounts of NSAIDs which aretherapeutically effective may be lower in the current invention thanotherwise found in practice due to potential positive kineticinteraction and NSAID absorption in the presence of an acid inhibitor.

Preferably, the pharmaceutical composition of the present invention isin the form of a tablet or capsule that has: (a) the acid inhibitorpresent in an amount effective to raise the gastric pH of a patient toat least 3.5 upon the administration of one or more unit dosage forms;and (b) the non-steroidal anti-inflammatory drug (NSAID) present in anamount effective to reduce or eliminate pain or inflammation in apatient upon administration of one or more of said unit dosage forms.The NSAID in the dosage form should be in a core, preferably a singlecore when tablets are used, that is surrounded by a coating that doesnot release NSAID until the pH of the surrounding medium is 3.5 orhigher. In the case of capsules, there may be several cores of NSAID,i.e., there may be multiple particles, each being surrounded by acoating that does not release NSAID until the pH of the surroundingmedium is 3.5 or higher. The acid inhibitor is in one or more layersoutside of the core which do not contain any NSAID. These layers are notsurrounded by an enteric coating and, upon ingestion of the tablet orcapsule by a patient, release the acid inhibitor into the patient'sstomach.

The term “unit dosage form” as used herein refers to a single entity fordrug administration. For example, a single tablet or capsule combiningboth an acid inhibitor and an NSAID would be a unit dosage form. A unitdosage form of the present invention preferably provides for coordinateddrug release in a way that elevates gastric pH and reduces thedeleterious effects of the NSAID on the gastroduodenal mucosa, i.e., theacid inhibitor is released first and the release of NSAID is delayeduntil after the pH in the GI tract has risen.

In a preferred embodiment, the unit dosage form is a multilayer tablet,having an outer layer comprising the acid inhibitor and an inner corewhich comprises the NSAID. In the most preferred form, coordinateddelivery is accomplished by having the inner core surrounded by apolymeric barrier coating that does not dissolve unless the surroundingmedium is at a pH of at least 3.5, preferably at least 4 and morepreferably, at least 5. Alternatively, a barrier coating may be employedwhich controls the release of NSAID by time, as opposed to pH, with therate adjusted so that NSAID is not released until after the pH of thegastrointestinal tract has risen to at least 3.5, preferably at least 4,and more preferably at least 5. Thus, a time-release formulation may beused to prevent the gastric presence of NSAID until mucosal tissue is nolonger exposed to the damage enhancing effect of very low pH.

One NSAID of special interest in dosage forms is aspirin which not onlyprovides relief from pain and inflammation but may also be used in lowdoses by patients to reduce the risk of stroke, heart attack and otherconditions. Thus, pharmaceutical compositions may contain an acidinhibitor in combination with aspirin in an amount effective, upon theadministration of one or more unit dosage forms, to achieve any of theseobjectives. As with the compositions described above the unit dosageform can be a tablet or capsule in which aspirin is present in a coreand is surrounded by a coating that does not release the aspirin untilthe pH of the surrounding medium is 3.5 or higher. The acid inhibitor isin one or more layers outside the core, which do not include an NSAID,are not surrounded by an enteric coating; and, upon ingestion of thedosage form by a patient, release the acid inhibitor into the patient'sstomach. Any of the acid inhibitors described herein may be used in theaspirin-containing dosage foams. In dosage forms designed for providinglow dose aspirin therapy to patients, the aspirin should typically bepresent at 20-200 mg.

The invention includes methods of treating a patient for pain,inflammation and/or other conditions by administering the pharmaceuticalcompositions described above. Although the method may be used for anycondition in which an NSAID is effective, it is expected that it will beparticularly useful in patients with osteoarthritis or rheumatoidarthritis. Other conditions that may be treated include, but are notlimited to: all forms of headache, including migraine headache; acutemusculoskeletal pain; ankylosing spondylitis; dysmenorrhoea; myalgias;and neuralgias.

In a more general sense, the invention includes methods of treatingpain, inflammation and/or other conditions by orally administering anacid inhibitor at a dose effective to raise a patient's gastric pH to atleast 3.5, preferably to at least 4 or and more preferably to at least5. The patient is also administered an NSAID, for example in acoordinated dosage form, that has been coated in a polymer that onlydissolves at a pH of at least 3.5, preferably at least 4 and, morepreferably, 5 or greater or which dissolves at a rate that is slowenough to prevent NSAID release until after the pH has been raised. Whenacid inhibitor and NSAID are administered in separate doses, e.g., intwo separate tablets, they should be given concomitantly (i.e., so thattheir biological effects overlap) and may be given concurrently, i.e.,NSAID is given within one hour after the acid inhibitor. Preferably, theacid inhibitor is an H2 blocker and, in the most preferred embodiment,it is famotidine at a dosage of between 5 mg and 100 mg. Proton pumpinhibitors may also be used and offer advantages in terms of duration ofaction. Any of the NSAIDs described above may be used in the method butnaproxen at a dosage of between 200 and 600 mg is most preferred. It isexpected that the acid inhibitor and analgesic will be typicallydelivered as part of a single unit dosage form which provides for thecoordinated release of therapeutic agents. The most preferred dosageform is a multilayer tablet having an outer layer comprising an H2blocker or a proton pump inhibitor and an inner core comprising anNSAID.

The invention also provides a method for increasing compliance in apatient requiring frequent daily dosing of NSAIDs by providing both anacid inhibitor and NSAID in a single convenient, preferably coordinated,unit dosage form, thereby reducing the number of individual doses to beadministered during any given period.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a four layer tablet dosage form. Thereis a naproxen core layer surrounded by a barrier layer. A third, entericcoating, layer delays the release of naproxen sodium until the pH is ata specific level, e.g., above 4. Finally, there is an outer layer thatreleases an acid inhibitor such as famotidine.

FIG. 2 illustrates a three layer dosage form. An acid inhibitor, e.g.,famotidine, is released immediately after ingestion by a patient inorder to raise the pH of the gastrointestinal tract to above a specificpH, e.g., above 4. The innermost layer contains naproxen. Thus, thedosage form has a naproxen core, an enteric film coat and an acidinhibitor film coat.

FIG. 3 illustrates a naproxen sodium pellet which contains a subcoat orbarrier coat prior to the enteric film coat.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based upon the discovery of improvedpharmaceutical compositions for administering NSAIDs to patients. Inaddition to containing one or more NSAIDs, the compositions include acidinhibitors that are capable of raising the pH of the GI tract ofpatients. All of the dosage forms are designed for oral delivery andprovide for the coordinated release of therapeutic agents, i.e., for thesequential release of acid inhibitor followed by analgesic.

The NSAIDs used in preparations may be either short or long acting. Asused herein, the term “long acting” refers to an NSAID having apharmacokinetic half-life of at least 2 hours, preferably at least 4hours and more preferably, at least 8-14 hours. In general, its durationof action will equal or exceed about 6-8 hours. Examples of long-actingNSAIDs are: flurbiprofen with a half-life of about 6 hours; ketoprofenwith a half-life of about 2 to 4 hours; naproxen or naproxen sodium withhalf-lives of about 12 to 15 hours and about 12 to 13 hoursrespectively; oxaprozin with a half life of about 42 to 50 hours;etodolac with a half-life of about 7 hours; indomethacin with ahalf-life of about 4 to 6 hours; ketorolac with a half-life of up toabout 8-9 hours, nabumetone with a half-life of about 22 to 30 hours;mefenamic acid with a half-life of up to about 4 hours; and piroxicamwith a half-life of about 4 to 6 hours. If an NSAID does not naturallyhave a half-life sufficient to be long acting, it can, if desired, bemade long acting by the way in which it is formulated. For example,NSAIDs such as acetaminophen and aspirin may be formulated in a mannerto increase their half-life or duration of action. Methods for makingappropriate formulations are well known in the art (see e.g. Remington'sPharmaceutical Sciences, 16^(th) ed., A. Oslo editor, Easton, Pa.(1980)).

It is expected that a skilled pharmacologist may adjust the amount ofdrug in a pharmaceutical composition or administered to a patient basedupon standard techniques well known in the art. Nevertheless, thefollowing general guidelines are provided:

-   -   Indomethacin is particularly useful when contained in tablets or        capsules in an amount from about 25 to 75 mg. A typical daily        oral dosage of indomethacin is three 25 mg doses taken at        intervals during the day. However, daily dosages of up to about        150 mg are useful in some patients.    -   Aspirin will typically be present in tablets or capsules in an        amount of between about 250 mg and 1000 mg. Typical daily        dosages will be in an amount ranging from 500 mg to about 10 g.        However, low dose aspirin present at 20-200 mg (and preferably        40-100 mg) per tablet or capsule may also be used.    -   Ibuprofen may be provided in tablets or capsules of 50, 100,        200, 300, 400, 600, or 800 mg. Daily doses should not exceed        3200 mg. 200 mg-800 mg may be particularly useful when given 3        or 4 times daily.    -   Flurbiprofen is useful when in tablets at about from 50 to 100        mg. Daily doses of about 100 to 500 mg, and particularly from        about 200 to 300 mg, are usually effective.    -   Ketoprofen is useful when contained in tablets or capsules in an        amount of about 25 to 75 mg. Daily doses of from 100 to 500 mg        and particularly of about 100 to 300 mg are typical as is about        25 to 50 mg every six to eight hours.    -   Naproxen is particularly useful when contained in tablets or        capsules in an amount of from 250 to 500 mg. For naproxen        sodium, tablets of about 275 or about 550 mg are typically used.        Initial doses of from 100 to 1250 mg, and particularly 350 to        800 mg are also used, with doses of about 550 mg being generally        preferred.    -   Oxaprozin may be used in tablets or capsules in the range of        roughly 200 mg to 1200 mg, with about 600 mg being preferred.        Daily doses of 1200 mg have been found to be particularly useful        and daily doses should not exceed 1800 mg or 26 mg/kg.    -   Etodolac is useful when provided in capsules of 200 mg to 300 mg        or in tablets of about 400 mg. Useful doses for acute pain are        200-400 mg every six-eight hours, not to exceed 1200 mg/day.        Patients weighing less than 60 kg are advised not to exceed        doses of 20 mg/kg. Doses for other uses are also limited to 1200        mg/day in divided doses, particularly 2, 3 or 4 times daily.    -   Ketorolac is usefully provided in tablets of 1-50 mg, with about        10 mg being typical. Oral doses of up to 40 mg, and particularly        10-30 mg/day have been useful in the alleviation of pain.    -   Nabumetone may be provided in tablets or capsules of between 500        mg and 750 mg. Daily doses of 1500-2000 mg, after an initial        dose of 100 mg, are of particular use.    -   Mefenamic acid is particularly useful when contained in tablets        or capsules of 50 mg to 500 mg, with 250 mg being typical. For        acute pain, an initial dosage of 1-1000 mg, and particularly        about 500 mg, is useful, although other doses may be required        for certain patients.    -   Lornoxicam is provided in tablets of 4 mg or 8 mg. Useful doses        for acute pain are 8 mg or 16 mg daily, and for arthritis are 12        mg daily.

Other NSAIDs that may be used include: celecoxib, rofecoxib, meloxicam,piroxicam, droxicam, tenoxicam, valdecoxib, parecoxib, etoricoxib,CS-502, JTE-522, L-745,337, or NS398. JTE-522, L-745,337 and NS398 asdescribed, inter alia, in Wakatani, et al. (Jpn. J. Pharmacol.78:365-371 (1998)) and Panara, et al. (Br. J. Pharmacol. 116:2429-2434(1995)). The amount present in a tablet or administered to a patientwill depend upon the particular NSAID being used. For example:

-   -   Celecoxib may be administered in a tablet or capsule containing        from about 100 mg to about 500 mg or, preferably, from about 100        mg to about 200 mg.    -   Piroxicam may be used in tablets or capsules containing from        about 10 to 20 mg.    -   Rofecoxib will typically be provided in tablets or capsules in        an amount of 12.5, 25 or 50 mg. The recommended initial daily        dosage for the management of acute pain is 50 mg.    -   Meloxicam is provided in tablets of 7.5 mg, with a recommended        daily dose of 7.5 or 15 mg for the management of osteoarthritis.    -   Valdecoxib is provided in tablets of 10 or 20 mg, with a        recommended daily dose of 10 mg for arthritis or 40 mg for        dysmenorrhea.

With respect to acid inhibitors, tablets or capsules may containanywhere from 1 mg to as much as 1 g. Typical amounts for H2 blockersare: cimetidine, 100 to 800 mg/unit dose; ranitidine, 50-300 mg/unitdose; famotidine, 5-100 mg/unit dose; ebrotidine 400-800 mg/unit dose;pabutidine 40 mg/unit dose; lafutidine 5-20 mg/unit dose; andnizatidine, 50-600 mg/unit dose. Proton pump inhibitors will typicallybe present at about 5 mg to 600 mg per unit dose. For example, theproton pump inhibitor omeprazole should be present in tablets orcapsules in an amount from 5 to 50 mg, with about 10 or 20 mg beingpreferred. Other typical amounts are: esomeprazole, 5-100 mg, with about40 mg being preferred; lansoprazole, 5-150 mg (preferably 5-50 mg), withabout 7.5, 15 or 30 mg being most preferred; pantoprazole, 10-200 mg,with about 40 mg being preferred; and rabeprazole, 5-100 mg, with about20 mg being preferred.

Making of Pharmaceutical Preparations

The pharmaceutical compositions of the invention include tablets,dragees, liquids and capsules and can be made in accordance with methodsthat are standard in the art (see, e.g., Remington's PharmaceuticalSciences, 16^(th) ed., A Oslo editor, Easton, Pa. (1980)). Drugs anddrug combinations will typically be prepared in admixture withconventional excipients. Suitable carriers include, but are not limitedto: water; salt solutions; alcohols; gum arabic; vegetable oils; benzylalcohols; polyethylene glycols; gelatin; carbohydrates such as lactose,amylose or starch; magnesium stearate; talc; silicic acid; paraffin;perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinylpyrrolidone; etc. The pharmaceutical preparations can be sterilized and,if desired, mixed with auxiliary agents such as: lubricants,preservatives, disintegrants; stabilizers; wetting agents; emulsifiers;salts; buffers; coloring agents; flavoring agents; or aromaticsubstances.

Enteric coating layer(s) may be applied onto the core or onto thebarrier layer of the core using standard coating techniques. The entericcoating materials may be dissolved or dispersed in organic or aqueoussolvents and may include one or more of the following materials:methacrylic acid copolymers, shellac, hydroxypropylmethcellulosephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosetrimellitate, carboxymethylethylcellulose, cellulose acetate phthalateor other suitable enteric coating polymer(s). The pH at which theenteric coat will dissolve can be controlled by the polymer orcombination of polymers selected and/or ratio of pendant groups. Forexample, dissolution characteristics of the polymer film can be alteredby the ratio of free carboxyl groups to ester groups. Enteric coatinglayers also contain pharmaceutically acceptable plasticizers such astriethyl citrate, dibutyl phthalate, triacetin, polyethylene glycols,polysorbates or other plasticizers. Additives such as dispersants,colorants, anti-adhering and anti-foaming agents may also be included.

The Making of Tablet Dosage Forms

Preferably, the combination of an acid inhibitor and an NSAID will be inthe form of a bi- or multi-layer tablet. In a bilayer configuration, oneportion of the tablet contains the acid inhibitor in the required dosealong with appropriate excipients, agents to aid dissolution,lubricants, fillers, etc. The second portion of the tablet will containthe NSAID, preferably naproxen, in the required dose along with otherexcipients, dissolution agents, lubricants, fillers, etc. In the mostpreferred embodiment, the NSAID layer is surrounded by a polymericcoating which does not dissolve at a pH of less than 4. The NSAID may begranulated by methods such as slugging, low- or high-shear granulation,wet granulation, or fluidized-bed granulation. Of these processes,slugging generally produces tablets of less hardness and greaterfriability. Low-shear granulation, high-shear granulation, wetgranulation and fluidized-bed granulation generally produce harder, lessfriable tablets.

EXAMPLES Example 1 Enteric Coated Naproxen Sodium Core and FamotidineImmediate Release

A schematic diagram of a four layer tablet dosage form is shown inFIG. 1. The first layer contains naproxen sodium distributed throughouta matrix of pharmaceutically acceptable fillers, excipients, bindingagents, disintegrants, and lubricants.

The second layer is a barrier layer which protects the first layercontaining naproxen sodium. The barrier film coat is applied byconventional pan coating technology and the weight of the barrier coatmay vary from 1% to 3% of the core tablet weight. In particularembodiments, the core naproxen sodium tablet is coated with coatingingredients such as Opaspray® K-1-4210A or Opadry® YS-1-7006 (Colorcon,West Point, Pa.). Polymer film coating ingredients such ashydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in acoating suspension may also be used.

The function of the third layer is to prevent the release of naproxensodium until the dosage form reaches an environment where the pH isabove about 4 or 5. The enteric coating does not dissolve in areas ofthe GI tract where the pH may be below about 4 or 5 such as in anunprotected stomach. Methacrylic acid copolymers are used as the entericcoating ingredient, triethyl citrate and dibutyl phthalate areplasticizers, and ammonium hydroxide is used to adjust the pH of thedispersion. The coating dissolves only when the local pH is above, forexample, 5.5 and, as a result, naproxen sodium is released.

The outermost layer contains an “acid inhibitor” in an effective amountwhich is released from the dosage form immediately after administrationto the patient. The acid inhibitor in the present example is a protonpump inhibitor or, preferably the H2 blocker famotidine, which raisesthe pH of the gastrointestinal tract to above 4. The typical effectiveamount of famotidine in the dosage form will vary from 5 mg to 100 mg. Atypical film coating formulation contains Opadry Clear® YS-1-7006 whichhelps in the formation of the film and in uniformly distributingfamotidine within the fourth layer without tablets sticking to thecoating pan or to each other during application of the film coat. Otheringredients may include: plasticizers such as triethyl citrate, dibutylphthalate, and polyethylene glycol; anti-adhering agents such as talc;lubricating ingredients such as magnesium stearate; and opacifiers suchas titanium dioxide. In addition, the pH of the film coating solutioncan be adjusted to aid in dissolution of the famotidine. The filmcoating is thin and rapidly releases famotidine for absorption.

Core Tablet Ingredients % W/W mg/Tablet Naproxen sodium, USP 74.074500.00 Microcrystalline cellulose, NF 17.166 115.87 (Avicel PH 200)Povidone (K29/32), USP 3.450 23.29 Talc, USP 4.350 29.36 MagnesiumStearate, NF 0.960 6.48 Total 100.00 675.00

Barrier Film Coating Ingredients % W/W Opadry Clear ® YS-1-7006 5.00Purified water USP 95.00 Total 100.00

Enteric Coating Dispersion Ingredients % W/W Methacrylic Acid Copolymer,NF 7.30 (Eudragit L-100-55) Methacrylic Acid Copolymer, NF 7.30(Eudragit L-100) Triethyl Citrate, NF 2.95 Dibutyl Phthalate, NF 1.17Ammonium Hydroxide (30%), NF 0.87 Purified water, USP 80.41 Total 100.00

Famotidine Coating Dispersion Ingredients % W/W Famotidine, USP 3.0Opadry Clear ® (YS-1-7006) 5.0 Talc, USP 3.0 Purified Water, USP 89.0Total 100.0

Example 2 Enteric Coated Naproxen Core and Famotidine Immediate Release

FIG. 2 illustrates a three layered dosage form which releases famotidineimmediately after ingestion by the patient in order to raise the pH ofthe gastrointestinal tract to above about 4. The innermost layercontains naproxen uniformly distributed throughout a matrix ofpharmaceutically acceptable excipients. These excipients performspecific functions and may serve as binders, disintegrants, orlubricants. A pharmaceutically acceptable enteric coating surrounds thenaproxen core. The function of the enteric coat is to delay the releaseof naproxen until the dosage form reaches an environment where the pH isabove about 4. The coating does not dissolve in the harshly acidic pH ofthe unprotected stomach. It contains methacrylic acid copolymers whichprevent the release of naproxen in the unprotected stomach. Alsoincluded are: triethyl citrate, a plasticizer; simethicone emulsion, ananti-foaming agent; and sodium hydroxide which is used to adjust the pHof the dispersion.

The outermost layer contains an “acid inhibitor” in an effective amountwhich is released from the dosage form immediately after administrationto the patient. The acid inhibitor in this example is a proton pumpinhibitor or, preferably, the H2 blocker famotidine which raises the pHof the stomach to above 4. A typical film coating formulation containsOpadry Clear® YS-1-7006 which helps in the formation of the film and inuniformly distributing famotidine in the fourth layer without tabletssticking to the coating pan or sticking to each other during applicationof the film coat. Other ingredients are: plasticizers such aspolyethylene glycol 8000; anti-adhering agents such as talc; lubricatingingredients such as magnesium stearate; and opacifiers such as titaniumdioxide. In addition, the pH of the film coating solution can beadjusted to aid in dissolution of the famotidine. The film coating isthin and rapidly releases famotidine for absorption.

Core Tablet Ingredients % W/W mg/Tablet Naproxen, USP 90.91 500.00Povidone K-90, USP 2.00 11.00 Starch, USP 2.59 14.25 CroscarmelloseSodium, USP 4.00 22.00 Magnesium Stearate, NF 0.50 2.75 Total 100.00550.00 Purified Water, USP qs

Enteric Coating Dispersion Ingredients % W/W Methacrylic Acid CopolymerType C, NF 14.5 (Eudragit L-100-55) Talc, USP 3.8 Sodium Hydroxide, NF0.2 Triethyl Citrate, NF 1.7 Simethicone Emulsion, USP 0.02 PurifiedWater, USP 79.78 Total 100.00

Famotidine Coating Dispersion Ingredients % W/W Famotidine, USP 3.0Opadry Clear ® (YS-1-7006) 5.0 Talc, USP 3.0 Purified Water, USP 89.0Total 100.0

Example 3 Naproxen Controlled Release Core and Famotidine ImmediateRelease

A trilayer tablet which separates famotidine contained in the film coatfrom controlled-release naproxen may be used in the present invention.The core tablet of naproxen is formulated using excipients which controlthe drug release for therapeutic relief from pain and inflammation for24 hours. FIG. 2 shows an example of an appropriate trilayer tablet. Inthis particular example, naproxen is mixed with a polymeric material,hydroxypropyl-methylcellulose and granulated with water. The granulesare dried, milled, and blended with a lubricant, such as magnesiumstearate. They are then compacted into tablets.

The controlled-release core tablet of naproxen is film coated with apharmaceutically acceptable enteric coating. The function of the entericcoat is to delay the release of naproxen until the dosage form reachesan environment where the pH is above about 4. The coating does notdissolve in the extremely acidic pH of the unprotected stomach. Thefunction of methacrylic acid copolymers is to prevent the release ofnaproxen until the pH of the stomach rises. Triethyl citrate is aplasticizer, simethicone emulsion is a anti-foaming agent, and sodiumhydroxide is used to adjust the pH of the dispersion.

The outermost layer contains an “acid inhibitor” which is released fromthe dosage form immediately after administration to the patient. Theacid inhibitor in the present example is a proton pump inhibitor or,preferably, the H2 blocker famotidine which consistently raises the pHof the stomach to above 4. The typical effective amount of famotidine inthe dosage will vary from 5 mg to 100 mg. A typical film coatingformulation contains Opadry Blue® YS-1-4215 which is essential for filmformation and for the uniform application of famotidine to the coretablet. Polymer film coating ingredients, hydroxypropylmethylcelluloseor Opaspray® K-1-4210A (Colorcon, West Point, Pa.) may also be used.Other ingredients which help in the formation of the film and in theuniform application of famotidine to the core tablet are: plasticizerssuch as triethyl citrate and dibutyl phthalate; anti-adhering agentssuch as talc; lubricating ingredients such as magnesium stearate; andopacifiers such as titanium dioxide. In addition, the pH of the filmcoating solution can be adjusted to aid in dissolution of thefamotidine. The film coating is thin and rapidly releases famotidine forabsorption.

Core Tablet Ingredients % W/W mg/Tablet Naproxen, USP 94.00 750Hydroxypropyl methylcellulose 5.00 39.9 2208, USP (viscosity 15000 cps)Magnesium Stearate, NF 1.00 7.95 Total 100.00 797.85

Enteric Coating Dispersion Ingredients % W/W Methacrylic Acid CopolymerType C, NF 14.5 (Eudragit L-100-55) Talc, USP 3.8 Sodium Hydroxide, NF0.2 Triethyl Citrate, NF 1.7 Simethicone Emulsion, USP 0.02 PurifiedWater, USP 79.78 Total 100.00

Famotidine Coating Dispersion Ingredients % W/W Famotidine, USP 2.0Opadry Blue ® (YS-1-4215) 10.0 Talc, USP 9.0 Purified Water, USP 79.0Total 100.0

Example 4 Naproxen and Famotidine Controlled Release Core and FamotidineImmediate Release

A trilayer tablet which separates famotidine contained in the film coatfrom controlled-release naproxen and famotidine may be used in thepresent invention. The core tablet of naproxen and famotidine isformulated using excipients which control the drug release fortherapeutic relief from pain and inflammation for 24 hours. FIG. 2 is anexample of an appropriate trilayer tablet. In this particular example,naproxen and famotidine are mixed with a polymeric material,hydroxypropylmethylcellulose and granulated with water. The granules aredried, milled, and blended with a lubricant, such as magnesium stearate.They are then compacted into tablets.

The controlled-release core tablet of naproxen and famotidine is filmcoated with a pharmaceutically acceptable enteric coating. The functionof the enteric coat is to delay the release of naproxen until the dosageform reaches an environment where the pH is above about 4. The coatingdoes not dissolve in the extremely acidic pH of the unprotected stomach.The function of methacrylic acid copolymers is to prevent the release ofnaproxen until the pH of the stomach rises. Triethyl citrate is aplasticizer, simethicone emulsion is a anti-foaming agent, and sodiumhydroxide is used to adjust the pH of the dispersion

The outermost later contains an “acid inhibitor” which is released fromthe dosage form immediately after administration to the patient. Theacid inhibitor in the present example is a proton pump inhibitor or,preferably, the H2 blocker famotidine which consistently raises the pHof the stomach to above 4. The typical effective amount of famotidine inthe dosage will vary from 5 mg to 100 mg. A typical film coatingformulation contains Opadry Blue® YS-1-4215 which is essential for filmformation and for the uniform application of famotidine to the coretablet. Polymer film coating ingredients, hydroxypropylmethylcelluloseor Opaspray® K-1-4210A (Colorcon, West Point, Pa.) may also be used.Other ingredients which help in the formation of the film and in theuniform application of famotidine to the core tablet are: plasticizerssuch as triethyl citrate and dibutyl phthalate; anti-adhering agentssuch as talc; lubricating ingredients such as magnesium stearate; andopacifiers such as titanium dioxide. In addition, the pH of the filmcoating solution can be adjusted to aid in dissolution of thefamotidine. The film coating is thin and rapidly releases famotidine forabsorption.

Core Tablet Ingredients % W/W mg/Tablet Naproxen, USP 88.05 500Famotidine, USP 3.52 20.0 Hydroxypropyl methylcellulose 7.03 39.9 2208,USP (viscosity 15000 cps) Magnesium Stearate, NF 1.40 7.95 Total 100.00567.85

Enteric Coating Dispersion Ingredients % W/W Methacrylic Acid CopolymerType C, NF 14.5 (Eudragit L-100-55) Talc, USP 3.8 Sodium Hydroxide, NF0.2 Triethyl Citrate, NF 1.7 Simethicone Emulsion, USP 0.02 PurifiedWater, USP 79.78 Total 100.00

Famotidine Coating Dispersion Ingredients % W/W Famotidine, USP 2.0Opadry Blue ® (YS-1-4215) 10.0 Talc, USP 9.0 Purified Water, USP 79.0Total 100.0

Example 5 Enteric Coated Naproxen Sodium Core and Pantoprazole ImmediateRelease in Film Coat

A schematic diagram of a four layer tablet dosage form is shown inFIG. 1. The first layer contains naproxen sodium distributed throughouta matrix of pharmaceutically acceptable fillers, excipients, bindingagents, disintegrants, and lubricants.

The second layer is a barrier layer which protects the first layercontaining naproxen sodium. The barrier film coat is applied byconventional pan coating technology and the weight of the barrier coatmay vary from 1% to 3% of the core tablet weight. In particularembodiments, the core naproxen sodium tablet is coated with coatingingredients such as Opaspray® K-1-4210A or Opadry® YS-1-7006 (Colorcon,West Point, Pa.). Polymer film coating ingredients such ashydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in acoating suspension may also be used.

The third layer is an enteric film coat. It does not dissolve in areasof the GI tract where the pH may be below 4 such as in an unprotectedstomach but it dissolves only when the local pH is above about 4.Therefore, the function of the third layer is to prevent the release ofnaproxen sodium until the dosage form reaches an environment where thepH is above 4. In this example, hydroxypropylmethylcellulose phthalateis the enteric coating ingredient, cetyl alcohol is a plasticizer andacetone and alcohol are solvents.

The fourth layer contains an “acid inhibitor” in an effective amountwhich is released from the dosage form as soon as the film coatdissolves. The acid inhibitor in this example is a proton pumpinhibitor, pantoprazole, which raises the pH of the gastrointestinaltract to above 4. The typical effective amount of pantoprazole in thedosage form may vary from 10 mg to 200 mg. The film coat is applied byconventional pan coating technology and the weight of film coat may varyfrom 4% to 8% of the core tablet weight. Other ingredients are,plasticizers such as triethyl citrate, dibutyl phthalate, anti-adheringagents such as talc, lubricating ingredients such as magnesium stearate,opacifiers such as, titanium dioxide, and ammonium hydroxide to adjustthe pH of the dispersion. The film coating is thin and rapidly releasespantoprazole for absorption. Therefore, pantoprazole releases first andthen the core erodes and releases naproxen sodium.

Core Tablet Ingredients % W/W mg/tablet Naproxen sodium, USP 74.075500.00 Microcrystalline cellulose, NF 17.165 115.87 (Avicel PH 200)Povidone (K29/32), USP 3.450 23.29 Talc, USP 4.350 29.36 MagnesiumStearate, NF 0.960 6.48 Total 100.00 675.00

Naproxen sodium, 50% microcrystalline cellulose and povidone are drymixed and wet granulated in an appropriate granulator with sufficientpurified water. The wet granules are dried, milled, and blended with theremaining 50% microcrystalline cellulose, talc and magnesium stearate.The final granule blend is compressed into tablets.

Barrier Film Coating Ingredients % W/W Opadry ® Clear YS-1-7006 5.00Purified Water, USP 95.00 Total 100.00

Opadry clear is added slowly to purified water and mixing is continueduntil Opadry is fully dispersed. The solution is sprayed on to thetablet cores in a conventional coating pan until proper amount of Opadryclear is deposited on the tablets.

Enteric Coating Ingredients % W/W Hydroxypropyl methylcellulosephthalate, NF 5.5 Cetyl alcohol, NF 0.3 Acetone, NF 66.3 Alcohol, USP27.9 Total 100.00

Hydroxypropylmethylcellulose phthalate and cetyl alcohol are dissolvedin a mixture of alcohol and acetone. The solution is then sprayed on tothe tablet bed in proper coating equipment. A sample of the tablets istested for gastric resistance and the coating stopped if the tabletspass the test.

Pantoprazole Film Coating Ingredients % W/W Pantoprazole sodium, USP5.00 Opadry ® Clear YS-1-7006 5.00 Sodium carbonate, NF 1.20 PurifiedWater, USP 88.80 Total 100.00

Pantoprazole sodium is dissolved in purified water containing sodiumcarbonate in solution. After thorough mixing, Opadry clear is addedslowly and mixing is continued until Opadry is fully dispersed. Thesuspension is sprayed on to the tablet cores in a conventional coatingpan until the proper amount of pantoprazole sodium is deposited.

Example 6 Enteric Coated Naproxen Sodium Core and Omeprazole ImmediateRelease in Film Coat

A schematic diagram of a four layer tablet dosage form is shown inFIG. 1. The first layer contains naproxen sodium distributed throughouta matrix of pharmaceutically acceptable fillers, excipients, bindingagents, disintegrants, and lubricants.

The second layer is a barrier layer which protects the first layercontaining naproxen sodium. The barrier film coat is applied byconventional pan coating technology and the weight of the barrier coatmay vary from 1% to 3% of the core tablet weight. In particularembodiments, the core naproxen sodium tablet is coated with coatingingredients such as Opaspray® K-1-4210A or Opadry® YS-1-7006 (Colorcon,West Point, Pa.). Polymer film coating ingredients such ashydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in acoating suspension may also be used.

The third layer is an enteric film coat. It does not dissolve in areasof the GI tract where the pH is below 4 such as in an unprotectedstomach but it dissolves only when the local pH is above 4. Therefore,the function of the third layer is to prevent the release of naproxensodium until the dosage form reaches an environment where the pH isabove about 4. In this example, hydroxypropylmethylcellulose phthalateis the enteric coating ingredient, cetyl alcohol is a plasticizer andacetone and alcohol are solvents.

The fourth layer contains an “acid inhibitor” in an effective amountwhich is released from the dosage form as soon as the film coatdissolves. The acid inhibitor in this example is a proton pumpinhibitor, omeprazole, which raises the pH of the gastrointestinal tractto above 4. The typical effective amount of omeprazole in the dosageform may vary from 5 mg to 50 mg. The film coat is applied byconventional pan coating technology and the weight of film coat may varyfrom 4% to 8% of the core tablet weight. Other ingredients are,plasticizers such as triethyl citrate, dibutyl phthalate, anti-adheringagents such as talc, lubricating ingredients such as magnesium stearate,opacifiers such as, titanium dioxide, and ammonium hydroxide to adjustthe pH of the dispersion. The film coating is thin and rapidly releasesomeprazole for absorption. Therefore, omeprazole is released first andthen the core erodes and releases naproxen sodium.

Core Tablet Ingredients % W/W mg/tablet Naproxen sodium, USP 74.075500.00 Microcrystalline cellulose, 17.165 115.87 NF (Avicel PH 200)Povidone (K29/32), USP 3.450 23.29 Talc, USP 4.350 29.36 MagnesiumStearate, NF 0.960 6.48 Total 100.00 675.00

Naproxen sodium, 50% microcrystalline cellulose and povidone are drymixed and wet granulated in an appropriate granulator with sufficientpurified water. The wet granules are dried, milled, and blended with theremaining 50% microcrystalline cellulose, talc and magnesium stearate.The final granule blend is compressed into tablets.

Barrier Film Coating Ingredients % W/W Opadry ® Clear YS-1-7006 5.00Purified Water, USP 95.00 Total 100.00

Opadry clear is added slowly to purified water and mixing is continueduntil Opadry is fully dispersed. The solution is sprayed on to thetablet cores in a conventional coating pan until the proper amount ofOpadry clear is deposited on the tablets.

Enteric Coating Ingredients % W/W Methacrylic Acid Copolymer, NF 6.0(Eudragit L-100-55) Triethyl Citrate, NF 0.6 Talc, USP 3.0 PurifiedWater, USP 5.0 Isopropyl Alcohol, USP 85.40 Total 100.00

Methacrylic acid copolymer, triethyl citrate, and talc are dissolved ina mixture of isopropyl alcohol and water. The solution is then sprayedon to the tablet bed in a proper coating equipment. A sample of thetablets is tested for gastric resistance and the coating is stopped ifthe tablets pass the test.

Omeprazole Film Coating Ingredients % W/W Omeprazole, USP 5.00 Opadry ®Clear YS-1-7006 5.00 Purified Water, USP 10.00 Isopropyl Alcohol, USP80.00 Total 100.00

Omeprazole is dissolved in a purified water and isopropyl alcoholmixture. After thorough mixing, Opadry clear is added slowly and mixingis continued until Opadry is fully dispersed. The suspension is sprayedon to the tablet cores in a conventional coating pan until proper amountof omeprazole is deposited on the tablets.

Example 7 Naproxen Sodium Delayed Release and Omeprazole ImmediateRelease Capsule

A coordinated delivery dosage may be used to provide fast release of anacid inhibitor, a proton pump inhibitor, omeprazole which raises the pHof the gastrointestinal tract to above 4, and the delayed release of anon-steroidal anti-inflammatory drug, naproxen sodium. Omeprazolegranules modify the pH of the stomach such that the drug readilydissolves and is absorbed in the stomach without significantdegradation. The typical effective amount of omeprazole in the dosageform may vary from 5 mg to 50 mg. The release of naproxen sodium isdelayed by enteric coating.

Omeprazole granules contain an alkalizing excipient such as sodiumbicarbonate. Other soluble alkalizing agents such as potassiumbicarbonate, sodium carbonate, sodium hydroxide, or their combinationsmay also be used. The alkalizing agent helps solubilize and protectomeprazole from degradation before its absorption. Sodium lauryl sulfatehelps in the wetting of omeprazole. Other surfactants may be used toperform the same function. In the present example, hydroxypropylmethylcellulose helps in granule formation, sodium starch glycolate is adisintegrant, and magnesium stearate is a lubricant. Other excipientsmay also be used to perform these functions.

Naproxen sodium pellets as shown in FIG. 3 are prepared by the wetmassing technique and the conventional extrusion and spheronizationprocess. The excipients used in the formulation are microcrystallinecellulose, and povidone. The pellets after drying and classification arecoated with a protective subcoating containing povidone. Other coatingingredients may also be used such as Opaspray K-1-4210A or OpadryYS-1-7006 (trademarks of Colorcon, West Point, Pa.). Polymer filmcoating ingredients such as hydroxypropylmethylcellulose 2910 andpolyethylene glycol 8000 in a subcoating suspension are alsoalternatives. Other ingredients are, plasticizers such as triethylcitrate, dibutyl phthalate, anti-adhering agents such as talc,lubricating ingredients such as magnesium stearate, opacifiers such as,titanium dioxide.

The subcoated pellets are enteric coated using enteric coating polymers.In this example, the enteric coating polymer is methacrylic acidcopolymer and the plasticizer is dibutyl phthalate which are dissolvedin a mixture of acetone and alcohol. The enteric film does not dissolvein the acidic pH but dissolves when the pH in the gut is above about pH6 and releases naproxen sodium.

mmmOmeprazole Granules % W/W mg/capsule Omeprazole, USP 12.9 20.00Sodium Bicarbonate, USP 82.40 127.72 Hydroxypropyl methylcellulose, USP2.00 3.10 Sodium lauryl sulfate, NF 0.20 0.31 Sodium starch glycolate,NF 2.00 3.10 Magnesium stearate, NF 0.50 0.77 Total 100 100

Hydroxypropylmethylcellulose is dissolved in water, then sodium laurylsulfate is added and the solution is mixed. Omeprazole, microcrystallinecellulose, and sodium bicarbonate are dry mixed together and granulatedwith the granulating solution. The granulation is mixed until propergranule formation is reached. The granulation is then dried, milled, andblended with magnesium stearate.

Pellet Ingredients % W/W mg/tablet Naproxen sodium, USP 86.80 250.00Microcrystalline cellulose, NF 11.10 32.00 (Avicel PH 200) Povidone(K90), USP 2.10 6.00 Total 100.00 288.00

Povidone is dissolved in water. Naproxen sodium and microcrystallinecellulose are dry mixed and granulated with povidone solution. The wetmass is mixed until proper consistency is reached. The wet mass is thenpressed through an extruder and spheronized to form pellets. The pelletsare then dried and classified into suitable particle size range.

Subcoat Ingredients % W/W Povidone (K29-32), USP 10.00 Alcohol, USP90.00 Total 100.00

The pellet cores are coated using povidone solution by a conventionalcoating pan method to a weight gain of 1-2%.

Enteric Coating Ingredients % W/W Methacrylic Acid Copolymer, NF 8.20(Eudragit L-100) Diethyl Phthalate, NF 1.70 Acetone, NF 33.30 IsopropylAlcohol, USP 56.80 Total 100.0

Eudragit L-100 is dissolved in isopropanol and acetone and diethylphthalate is dissolved. The solution is sprayed on the pellet coresusing proper film coating equipment. A sample of the pellets is testedfor gastric resistance before stopping the coating process.

Omeprazole fast release granules and naproxen sodium delayed releasepellets are blended together and filled into appropriate size capsulesto contain 250 mg naproxen sodium and 20 mg omeprazole per capsule.

Example 8 Naproxen Delayed Release and Omeprazole Immediate ReleaseCapsule

The present Example is directed to a coordinated delivery dosage formcontaining omeprazole and naproxen. The formulation contains 10 mgomeprazole and uses methylcellulose as a binder and croscarmellosesodium as a disintegrant. Naproxen pellets as shown in FIG. 3 do notneed a subcoating layer and are enteric coated with an aqueousdispersion of methacrylic acid copolymer. Optionally, these pelletscould be compressed into a core and film coated with an acid inhibitorand thereby form a bilayer tablet.

Omeprazole Granules % W/W mg/capsule Omeprazole, USP 6.45 10.00 SodiumBicarbonate, USP 88.85 137.71 Methylcellulose, USP 2.00 3.10 Sodiumlauryl sulfate, NF 0.20 0.31 Croscarmellose sodium, NF 2.00 3.10Magnesium stearate, NF 0.50 0.78 Total 100 100

Methylcellulose is dissolved in water, then sodium lauryl sulfate isadded to the solution and mixed. Omeprazole, microcrystalline cellulose,and sodium bicarbonate are dry mixed together and granulated with thegranulating solution. The granulation is mixed until proper granuleformation is reached. The granulation is then dried, milled, and blendedwith magnesium stearate.

Pellet Ingredients % W/W mg/tablet Naproxen, USP 76. 250.00Microcrystalline cellulose, NF 21. 71.44 (Avicel PH 200) Povidone (K90),USP 2. 6.56 Total 100. 328.00

Povidone is dissolved in water. Naproxen and microcrystalline celluloseare dry mixed and granulated with povidone solution. The wet mass ismixed until proper consistency is reached. The wet mass is then pressedthrough an extruder and spheronized to form pellets. The pellets arethen dried and classified into a suitable particle size range.

Enteric Coating Ingredients % W/W Methacrylic Acid Copolymer, NF(Eudragit 15.60 L30D 30% dispersion) Talc, USP 7.60 Triethyl citrate, NF1.60 Simethicone Emulsion, USP 0.20 (Silicone antifoam emulsion SE 2)Purified Water, USP 74.80

Eudragit 30D is dispersed in purified water and simethicone emulsion.Talc and triethyl citrate are then dispersed. The suspension is sprayedon the pellet cores using proper film coating equipment. A sample of thepellets is tested for gastric resistance before stopping the coatingprocess. Omeprazole fast release granules and naproxen sodium delayedrelease pellets are blended together and filled into appropriate sizecapsules to contain 250 mg naproxen and 10 mg omeprazole per capsule.

Example 9 Clinical Study of the Relationship of Gastric pH toNSAID-Induced Gastric Ulcers

Sixty-two subjects were enrolled in a clinical study and randomlyassigned to three groups. The following three groups were administeredstudy medication twice daily for five days: (a) 550 mg naproxen sodium(n=10), (b) 40 mg famotidine given with 550 mg of naproxen or famotidinefollowed 90 minutes later by 550 mg naproxen, (n=39) or (c) 20 mgomeprazole followed by 550 mg naproxen sodium (n=13). Gastric pH wasmeasured hourly beginning at the time of dosing of the final daily doseof study medication and for 8-10 hours thereafter. Subjects had agastric endoscopy performed at the beginning and on Day 5 prior to themorning dose of study medication to identify gastric and duodenalirritation; no subjects were admitted to the study if gastric irritationwas present at the time of initial endoscopy.

Five patients, three (33%) in the naproxen alone group and two (5%) inthe famotidine/naproxen group, presented with gastroduodenal ulcers atthe end of the study. In the naproxen alone group, the pH was greaterthan 4 only 4% of the time, and in the famotidine/naproxen group the pHwas greater than 4 forty-nine percent of the time during the 8-10 hoursfollowing naproxen sodium dosing. Additionally, Lanza grade 3 or 4damage was present in 28% (n=11) of the subjects receivingfamotidine/naproxen sodium, and present 100% (n=10) in the naproxensodium treatment group. Monitoring of gastric acidity on day 5 indicatedthat patients with Lanza scores of greater than 2 had integrated gastricacidity of greater than 100 mmol-hr./L. Only 20-40% of patients withintegrated gastric acidity of less than 100 mmol-hr/L had gastricpathology, whereas all patients with integrated gastric acidity greaterthan 100 mmol-hr/L had pathology.

Example 10 Famotidine and Enteric Coated Naproxen Reduce GastroduodenalDamage Due to NSAID Therapy

Thirty-seven patients were randomized to two groups for a one week studyof twice-daily dosing of: 500 mg enteric coated naproxen, and 500 mgenteric coated naproxen preceded by 40 mg famotidine. Endoscopies wereconducted on all patients prior to first dosing and on the final day ofthe study. No subjects had evidence of gastroduodenal damage at thebeginning of the study (at first endoscopy).

At the second endoscopy, Lanza scores for gastroduodenal damage wereassessed for all subjects. 39% of the subjects in the enteric coatednaproxen 500 mg group had grade 3-4 gastroduodenal damage. This is lowerthan the percentage that would be expected for the administration of 500mg of non-enteric naproxen based upon previous work. Nevertheless,subjects administered 500 mg enteric coated naproxen and 40 mgfamotidine had an even lower incidence of grade 3-4 gastroduodenaldamage (26%) than subjects who had previously taken enteric coatednaproxen alone which demonstrates the value of combining acid inhibitionwith enteric coating of NSAID to minimize the gastrointestinal damage.

All references cited herein are fully incorporated by reference. Havingnow fully described the invention, it will be understood by those ofskill in the art that the invention may be performed within a wide andequivalent range of conditions, parameters and the like; withoutaffecting the spirit or scope of the invention or any embodimentthereof.

What is claimed is:
 1. A pharmaceutical composition in unit dosage formcomprising therapeutically effective amounts of: (a) esomeprazole,wherein at least a portion of said esomeprazole is not surrounded by anenteric coating; and (b) naproxen surrounded by a coating that inhibitsits release from said unit dosage form unless said dosage form is in amedium with a pH of 3.5 or higher; wherein said unit dosage formprovides for release of said esomeprazole such that upon introduction ofsaid unit dosage form into a medium, at least a portion of saidesomeprazole is released regardless of the pH of the medium.
 2. Thepharmaceutical composition of claim 1, wherein naproxen is present insaid unit dosage form in an amount of 200-600 mg.
 3. The pharmaceuticalcomposition of claim 1, wherein esomeprazole is present in said unitdosage form in an amount of from 5 to 100 mg.
 4. The pharmaceuticalcomposition of claim 1, wherein naproxen is present in said unit dosageform in an amount of between 200-600 mg and esomeprazole in an amount offrom 5 to 100 mg per unit dosage form.